Colon Cancer Screening Trends. U.S. Cancer Stastistics 2010

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1 ACG Annual Meeting Emily Couric Memorial Lecture Colon Cancer Screening Evolution to Eradication David A. Johnson MD FACG Professor of Medicine Chief of Gastroenterology Eastern VA Medical School Norfolk VA Colon Cancer Screening Trends NCI study % follows all the recommended CRC guidelines Over/under utilization J Gen Intern Med (in press) Focused Questions Screening trends and impacts Changing demographics and relative risks Current data results/success/failure Direction for failure resolution Future Colon Cancer Screening Evolution to Eradication U.S. Cancer Stastistics 2010 CA Cancer J Clin 2010; 60: Colon Cancer Screening Trends CA Cancer J Clin U.S. 2010; Cancer 60: Statistics 2010 U.S. Cancer Stastistics Estimates New cases CRC 143,000+ CRC Deaths 51,000+ CA Cancer J Clin 2010; 60:

2 New Risk Factors for CRC Increase by 50% Obesity/metabolic syndrome Adenomas CRC Cigarette smoking -Threshold dose (30-35 yr induction) -Risk reduction requires 20 yrs abstinence Increase by 2-3x adenoma and CRC Same risk as FDR with CRC CRC- Ethnic Risk Prevalence risks for polyps >9mm Men 38% Women 43% Sub-analysis for >60 yrs higher prevalence - Black men (p=0.03) - Black women (p<0.001) Earlier onset/more aggressive disease Average risk screening at 45 Gastroenterology 2008;135: JAMA 2008;300(12): New Risk Factors for CRC Coronary artery disease Diabetes Exact risk weighting unclear Confounding risks overlapping Increase advanced neoplasia Metabolic syndrome/smoking overlap Colon Cancer Screening Tests State of the Evolving Art Gastroenterology 2008;135: CRC- Ethnic Risk Since 1985 incidence rates -Whites declined 20-25% - Blacks Men increased Women unchanged Mortality for blacks higher than whites 7.7 vs 6.2% p<0.001 JAMA 2008;300(12): Fecal Immunochemical Testing Is FIT for Widespread Use OC-Sensa Micro FIT Guaiac-Based Test Fecal Immunochemical Test (100 ng/ml cutpoint) Sensitivity Specificity Sensitivity Specificity 13.6% 92.4% 33.9% 90.6% Advanced adenomas Cancer 30.8% 92.4% 92.3% 90.1% Advanced 16.7% 92.9% 44.4% 82.1% colorectal neoplasias Am J Gastroenterol 2010 Sep; 105:2017 2

3 FIT for Prime Time? FIT should replace FOBT -ACG guidelines -ACS/MSTF guidelines Wide performance characteristics Careful evaluation of test variants Ann Intern Med 2009;150: $tool DNA Testing for $creening? CMS evaluation for National Coverage Decision PreGen-Plus (23 markers) APC Screening with stool DNA cost effective K-ras P53 - per test cost $40-60 q 3 yrs BAT-26 Cost effective at $350 if: DIA -adherence at least 50% greater than other tests No levels sensitivity/specificity Cost effective at $350 Ann Intern Med 2010; 153: FIT for Interim Use in Colonoscopy Surveillance Schedule? 1736 patients -+Family history -+Prior polyps 1071 asymptomatic had at least 1 FIT detecting: -Cancer (12/14) 86% sensitivity -Advanced adenoma (60/96) 63% sensitivity Diagnoses made earlier Repeated negative FIT Gastroenterology 2010 (in press) Cancer 25 months AA 24 months 2x reduced risk Cancer/AA Flexible Sigmoidoscopy Back to the Future? NORCCAP-1 trial interim results -intent to screen >55,000 randomized -FS vs. standard observation No CRC mortality difference 7rs f/u Lower data from case control studies CRC reduced incidence 76% CRC mortality reduced 59-79% 5% colonoscopy referral BMJ 2009;338:b1946 Lancet 2010;375: Stool DNA Testing Time for Science of CRC? Version 2 assay (DIA + vimentin) cancer detection - Sensitivity 87.5% No variance for location of CRC - Specificity 82.0% False + related to age Tissue study differentiation from normal - CRC - Advanced adenoma/serrated adenoma > 1 cm Fecal panel testing to begin 2011 Sensitivity 100% Specificity 100% Clin Gastro Hepatol 2007;5: American Assoc Clin Chem Anaheim CA July 2010 Flexible Sigmoidoscopy Back to the Future? UK screening -randomized controlled trial 2:1-112,239 controls and 57,099 FS patients Reduced with FS CRC incidence 23% CRC mortality 31% BMJ 2009;338:b1946 Lancet 2010;375:

4 Forthcoming trials Flexible Sigmoidoscopy Back to the Future? NCI PLCO Italian Score trial Computer Assisted Diagnosis (CAD) Effective when radiologists must detect: - small lesions that occur infrequently - mammography or with pulmonary nodules Purpose of CAD use in CTC is to -locate possible polyps automatically - annotate images Reader of CAD reviews the output -establishes the final diagnosis BMJ 2009;338:b1946 Lancet 2010;375: BE for CRC Screening Computer-aided detection (CAD) CT Colography CT colonographic studies in 30 patients -6 institutions 7 less-experienced readers -2 institutions -before and after CAD 39 total polyps and six depicted no polyps Sensitivity improved with CAD -from to (P=.0152). KEY ELEMENT-- TAKE OUT HUMAN VARIABILITY, LEARNING CURVES/EXPERIENCE Radiology. 2007;245(1):140-9 Improve sensitivity of less-experienced readers CTC with CAD CTC for Screening CRC Can it get better? What is the future? CAD marking VC OC Courtesy of Beth McFarland 4

5 CTC with CAD Reduced False Positive Findings? Large number of false + Developed MTANNs :massive training artificial neural networks Reduction in false (+) by 63% Med phys 2008;35(2): Haustral folds Residual stool Rectal tube IC valve Extracolonics Electronic Cleansing Cathartic and Non-cathartic CTC Electronic stool subtraction Digital subtraction bowel cleansing CT software distinguishes between: -tagged feces vs polyps vs fold Signature shapes for certain structures -Teach computer to recognize May make cathartic bowel prep obsolete -Only in early clinical stages of evaluation Med Phys 2008;35(7): Innovations in Prep Enhance CTC Compliance? Reduced or no prep Electronic cleansing CTC- Radiologic Advances Challenges Radiation reduction CTC- Good Fecal Tagging Cancer Risk Single CT Scan Cancer-related death one abdominal CT scan 0.06% for a patient exposed at 25 years of age 0.02% for a patient exposed at age 50 Lifetime radiation risk Most common radiogenic cancers Lung and colon cancer 10 msv exposure = risk of death N Engl J Med 2007;357:

6 Fully Automatic CAD-CTC Standard and Low Dose Radiation Automatic colon segmentation Candidate surface extraction Feature extraction No difference Sensitivity polyps >1 cm= 100% Sensitivity polyps 5-9 mm= 92% Sensivity polyps <5 mm=57% Standard vs Low Dose Radiation Colonoscopy Prevention/Protection Fewer deaths -10,292 cases (719 colonoscopies) - 51,460 controls (5031 colonoscopies) Yes: Left sided cancers OR 0.33 (CI: ) No: Right sided cancers OR 0.99 (CI: ) IEEE Trans Biomed End 2008;55(3): Ann Intern Med 2009;150:1-8 J Nat Cancer Inst 2010;102:89-95 Colonoscopy Prevention/Protection COLONOSCOPY=NO CRC SO WHAT S THE PROBLEM? GOOD NEWS BAD NEWS Splenic/descending Fewer deaths OR 0.36 (CI: ) Sigmoid -10,292 cases (719 colonoscopies) OR 0.29 (CI: ) Rectum - 51,460 controls (5031 colonoscopies) OR 0.07 (CI: ) Fewer cancers OR 0.52 (CI: ) patients (cross sectional analysis) Cecum/ascending Yes: Left sided OR cancers 0.99 OR (CI: ) 0.33 (CI: ) Hepatic flex/transverse OR 1.21 (CI: ) Ann Intern Med 2009;150:1-8 J Nat Cancer Inst 2010;102:89-95 Colonoscopy and CRC Mortality Ontario cohort 2,412,077 patients (50-90 yrs) -Multivariable hazard ratios for CRC death 1% increase complete colonoscopy=3% death Why Colonoscopy is Imperfect Uncontrollable Factors(Biologic Variances) Demographic factors (e.g. obesity/smoking) Rapidly growing polyps/tumors Increased risk of MSI in interval cancers Am J Gastroenterol 2010;105:

7 Why Colonoscopy is Imperfect Controllable Factors Ineffective application technology - suboptimal examination technique - suboptimal/insufficient time Technical limitations of colonoscopy Hidden mucosa Flat lesions Ineffective polypectomy Ineffective bowel preparation All controllable variables with current technology Bottom Line Withdrawal Time =Quality? Quantify the effect -suggested procedure time (no WD time data) -accounts 1/3 third of the variation in detection ADR is the prime measure but. -WD time should be recorded -available if ADR is low Rapidly becoming a standard of care of issue Gastrointest Endosc 2009; 69(7): ) Quality Colonoscopy What s the Problem? Wide variations performance/outcomes Missed cancers by PCPs >GIs GIs-variance adenoma and CRC detection Higher complication rate for low volume colonoscopists Even for GIs: Time of day variance ADR progressively declined hourly am vs pm Absolute difference of 11.8% Adenoma/CRC Detection Beauty in the Eyes of the Beholder? 110,402 negative complete colonoscopy -15-year follow-up period (14.5%) developed CRC If colonoscopy by non-gi Risk of incident CRC increased 40% HR 1.389; 95% CI, Clin Gastroenterol Hepatol 2010;8(3):275-9 Bottom Line Withdrawal Time =Quality? Recent data? WD time not predictive Literature is otherwise overwhelmingly consistent that it is Adenoma/CRC Detection Beauty in the Eyes of the Beholder? 4,883 CRCs within 3 yrs index colonoscopy -Grade, histology, stage= no difference 7.9% missed CRCs 4.5% rectal (men) 14.5% transverse (women) Gastrointest Endosc 2009; 69(7): ) Clin Gastroenterol Hepatol 2010;8(3):

8 Adenoma/CRC Detection Beauty in the Eyes of the Beholder? Predictors of missed CRCs Proximal location CRC Prior colonoscopy with polyp Exam by family practictioner - OR 1.59 ( ) Clin Gastroenterol Hepatol 2010;8(3):275-9 Is Biology to Blame? See No Evil.Serrated Lesions Serrated cancers BRAF mutation common + Inactivation % all multiple CRC tumor suppressor genes Cancers ->30% predominantly interval cancers right sided/poor differentiation 2 major pathways for adenoca Inactivation k-ras Silencing of DNA repair gene MGMT Distal cancers Am J Gastroenterol 2009; 104: Gastroenterology 2010 (in press) Quality Indicators Risks Interval CRC Poland CRC screening database : 45,206 patients/ 186 endoscopists Adenoma detection rate correlate with CRC Hazard ratios for adenoma detection >20% <11% HR % HR % HR N Engl J Med 2010;362: p= Is Biology to Blame? See No Evil.Serrated Lesions Serrated cancers common % all CRC ->30% interval cancers 2 major pathways for adenoca Large (>1cm) serrated adenoma -Marker for advanced CR neoplasia (OR 3-4x) Greater risk than 1-3 tubular adenomas Am J Gastroenterol 2009; 104: Gastroenterology 2010 (in press) Is Biology to Blame? See No Evil.Serrated Lesions Serrated cancers common % all CRC ->30% interval cancers 2 major pathways for adenoca Is Biology to Blame? Prevalence of Serrated Lesions Increased prevalence? Increased awareness and careful evaluation? Am J Gastroenterol 2009; 104: Gastroenterology 2010 (in press) 8

9 Quality and QUALITY Retrospective cohort average risk screening colo 15 GIs- 2 academic endoscopy units 11,049 polyps/ 6681 colonoscopies - 13% exams found > proximal serrated polyp (SP) Detection of SP correlated Range 1%-18% Detection of proximal serrated polyps varied Adenoma Endoscopist detection dependent rates (p=0.0005) Colonoscopy and CRC Screening Optics the Answer? Wide angle/high definition vs SC (RCT) Narrow band imaging vs SC (RCT) No difference High definition chromocolo vs white light (RCT) Gastroenterology 2008; Gastroenterology 2009;136: Am J Gastroenterol 2010;105: Gastrointest Endosc 2010;72: No difference Modest increase Flat and small adenomas Same for advanced adenomas Beating the Poor Prep Divide and Conquer RCT split vs same day dose Colon preformed within 8 hrs (P<0.001) Split dose vs same day gastric volume residual No difference Gastrointest Endosc Aug;72(2): Gastrointest Endosc Sep;72(3): Am J Gastroenterol 2010 Sep; 105:1954 Split dose superior p= ACG guidelines Clears up to 2 hrs before Colonoscopy and CRC Screening Optics the Answer? Cap fitted/high definition Miss rates reduced All adenomas 21 vs 33 % (p=0.039) Adenomas <6 mm 22 vs 35% (p=0.037) Gastroenterology 2008; Gastroenterology 2009;136: Am J Gastroenterol 2010;105: Gastrointest Endosc 2010;72: Modest increase Flat and small adenomas Same for advanced adenomas Beating the Poor Prep Divide and Conquer Split dose vs Morning of split dose -1 liter pm and 4 hrs before or 7 and 4 hrs before PM/AM= AM/AM AM/AM better: Night sleep Less day before interferance Less pain Gastrointest Endosc Aug;72(2): Gastrointest Endosc Sep;72(3): Am J Gastroenterol 2010 Sep; 105:1954 High Quality Colonoscopy Evaluating Options for GI THIRD EYE GIE 2010;71:551-6 GIE 2010; 71;

10 High Quality Colonoscopy Evaluating Options for GI THIRD EYE ADR(overall) increase 11.0% ADR >6mm increase 25% ADR>10mm increase 33.3% Right colon :14.9% Left colon: 4.1% GIE 2010;71:551-6 GIE 2010; 71; Disconnected Colonoscopy Capsule 545 patients sequential CCE/colonoscopy CCE accuracy for detection of polyps -39% (95% CI 30 48) sensitivity 6 mm -88% (95% CI 85 91) specificity -47% (95% CI 37 57) PPV -85% (95% CI 82 88) NPV Aliment Pharmacol Ther 2010; 32: Incomplete Polypectomy The Butcher to Blame? 35% of interval cancers at prior polypectomy sites Minneapolis VA: 12/45 (5 < 1cm) Chemoprevention / PPT: 11/32 (3 < 1 cm) Possible factors: Small polyps: biopsy versus snare Large polyps: piecemeal vs en bloc Clin Gastroenterol Heptatol 2006; 4: Gastrointest Endosc 2005;61;385-9 Gastroenterology 2005; 129:34-9 Disconnected Colonoscopy Capsule 545 patients sequential CCE/colonoscopy CCE accuracy for detection of polyps -39% (95% 5 CI cancers 30 48) colonoscopy sensitivity 6 mm -88% (95% 3 CI cancers 85 91) CCE specificity -47% (95% CI Sensitivity 37 57) PPV better -85% (95% Good/excellent CI 82 88) NPV prep Re-review by expert panel Not ready for prime time Aliment Pharmacol Ther 2010; 32: Piecemeal Polypectomy: Recurrence Sessile lesions > 2 cm: 10 western studies: 15-55% Piecemeal + APC tx: 10-21% Piecemeal +/- APC Visual recurrence: 17.6% Microscopic: 5.8% EMR of 421 polyps Piecemeal: 17 % En bloc : 6 % 1. Khashab M, Rex D. GIE 2009; 70: Booker J, GIE 2002; 55: Woodward T, DDW Abstract 683 The omics era Systems Biology /Molecular Pathology Genomics Transcriptomics Proteomics Metabolomics Expression signatures Volatile organic compounds Discriminate normal/neoplasia Reliable biomarkers lacking -enable screening -primary prevention Challenges Specific abnormalities to all Unique to targeted focus (neoplasm specific) Well characterized study population Mutat Res Aug 5- in press Br J Cancer Month in press 10

11 Conclusions Expanding/improving menu of screening options Risks for CRC and related death remain high Demographic changes evident Obesity,smoking, age, CAD,DM Emily Couric Think about it carefully If you believe it is the right thing to do THEN JUST DO IT! Conclusions Biologic changes evident Colonoscopy remains gold standard -Appropriate challenges for consistent quality Serrated neoplasms Colon Cancer Screening Evolving but not yet to Eradication Thank You! DO IT BETTER Colon Cancer Screening Efforts= Eradication Let s all..do IT! Quality Colonoscopy: Importance of Early Detection 11